Dihydropyrimidopyridazine derivatives

ABSTRACT

COMPOUNDS OF THE FORMULA 1-(Y-C(-X)(-Z)-)IMIDAZOLE WHEREIN R1 IS AN AROMATIC HYDROCARBON OR HETEROCYCLIC GROUP, SUCH AS PHENYL OR THIENYL, AND R2 IS A SECONDARY OR TRTIARY AMINE GROUP, SUCH AS PIPERIDINO, CYCLOHEXYLAMINO, AILINO OR ISOPPROPYLAMINO, HAVE EFFECTIVE DIURETIC ACTIVITY.

United States Patent C ce 3,787,414

Patented Jan. 22, 1974 The dihydropyrimido[4,5-d]pyridazine derivativesof 3,787,414 the present invention are those represented by the following general formula Shoyrro Yurugl, Kyoto, and Shintaro Klkuchl, Hyogo,

Japan, assignors to Takeda Chemical Industries, Ltd.,

Osaka, Japan No Drawing. Filed Oct. 4, 1971, Ser. No. 186,447 R: Claimspriority, application Japan, Oct. 14, 1970, N

Int. Cl. c070 87/40 US. Cl. 260-246 B 14 Claims HN\ N C HI ABSTRACT OFTHE DISCLOSURE R1 [11 Compounds of the formula 15 wherein R stands foran aromatic hydrocarbon or heterocyclic group, which is unsubstituted orsubstituted, R R stands for a secondary amino group or a tertiary aminor group, or their 1,4-dihydro isomers and their pharmaceu- HN l 1;tically acceptable salts.

\ In the General Formula I, the aromatic hydrocarbon H1 residuerepresented by symbol R includes that having up 2 to 10 carbon atomssuch as phenyl, naphthyl.

The heterocyclic group represented by symbol R includes 5 to 6-memberedmonocyclic ones containing one hetero atom of N, S and 0. Typicalexamples of the groups are, for example, furyl, thienyl or pyridyl. Thesubstituents of the above-mentioned aromatic hydrocarbon residue orheterocyclic group may, for instance, be a. lower alkyl (e.g. methyl,ethyl, propyl, isopropyl), halo- The Present invention relates to novely py gen (i.e. chlorine, bromine, fluorine, iodine) and a heterowhereinR is an aromatic hydrocarbon or heterocyclic group, such as phenyl orthienyl, and R is a secondary 25 or tertiary amine group, such aspiperidino, cyclohexylamino, anilino or isopropylamino, have effectivediuretic activity.

PY derivatives and their Pharmaceutically P cyclic group such as 5 or 6membcred heterocyclic group able salts, which have efiective diureticaction. containing one or two hetero atoms of N, S and O (e.g.

The present invention also relates to a process for the morpholino,piperazino, pyrrolidino).

production of these dihvdropyrimidopyridazin r va- The secondary ortertiary amino group represented by tives. symbol R includes a cyclicamino group, a monoor di- There have been synthesized many kinds ofdiuretics, alkylamino group, a monocycloalkylamino group, mono and someof them have been applied to Practical 118e, arylamino group and amonoaralkylamino group, the altypical examples of which arechlorothiazide derivatives, kyl or cycloalkyl being preferably a lowerone having up acetazolamide, triameterene, trifrocine, furosemide, etc.40 to 5 carbon atoms (e g. methyl, ethyl, propyl, isopropyl, However,known diuretics are not very satisfactory in butyl, t-butyl, amyl,hexyl, cyclohexyl, cyclopentyl, etc.)

view of one or more of such drawbacks as promoting the and the aryl oraralkyl being preferably that having up excretion of potassium as wellas sodium, causing side to 10 carbon atoms (e.g. phenyl, naphthyl,benzyl, phenefiects (e.g. increase of blood glucose level and blood uricylethyl, etc.).

acid level) P long-term administration, and Showing These secondary ortertiary amino groups may contain rather low diuretic activity andrather high toxicity. one or more substituents such as lower alkyls(e.g. methyl,

Under these circumstances, the present inventors have ethyl), aralkyl(e.g. benzyl), hydroxy and lower alkoxy made extensive studies forproviding effective diuretics (e.g. methoxy, ethoxy). accompanied withno such drawback as above. The cyclic amino group includes, forinstances, pyr- As the result of their studies, the present inventorshave rolidino, piperidino, morpholino, piperazino, N-methylsucceeded insynthesizing novel dihydropyrimido[4,5-d] piperazino,N-benzylpiperazino.

pyridazine derivatives, and found out that these com- The monoordialkylamino group includes, for instance, pounds can answer thepurpose. methylamino, ethylarnino, propylamino, isopropylamino,

The present inventors also found out that the acid adbutylamino,dimethylamino, diethylamino, methylethyldition salts of these compoundshave high solubility in amino, 2-ethoxyethylamino, 2-methoxyethylamino,N- water and the aqueous solutions of these acid additionmethyl-Z-hydroxyethylamino. The monocycloalkylamino salts are verystable for a relatively long period of time. group includes, forexample, cyclohexylamino. The mono- Therefore, these compounds are ofgreat advantage to use arylamino includes, for example, anilino,naphthylamino. in the form of injectable solutions. The aralkyl aminogroup includes, for example, benzyl- The present invention has beenaccomplished on the amino, N-benzyl-Z-hydroxyethylarnino. basis of thosefindings. The pharmaceutically acceptable salts of the present Thus, theprincipal object of the present invention is compounds include additionsalts with an inorganic acid to provide noveldihydropyrimido[4,5-d]pyridazine desuch as hydrochloric acid, sulfuricacid, nitric acid, phosrivatives useful as effective and improveddiuretics. Anphoric acid, etc. and with an organic acid such as oxalicother object is to provide a method for the production acid, maleicacid, malic acid, tartaric acid, methanesulfonic of these novelcompounds. acid, ethanesulfonic acid, etc.

Typical compounds represented by the General Formula I are exemplifiedbelow: i

(4) 2-pheny1-3,4-dihydro-5,8 bis(N benzylpiperazzino)-pyrimido[4,S-dlpyridazine (S) 2-phenyl-3,4-dihydro-5,8bis(ethylamino)pyrimido- [4,5-d1pyridazine (6)2-phenyl-3,4-dihydro-5,8-bis(benzylamino)pyrimido- [4,5-d1pyridazine (7)2-phenyl-3,4-dihydro 5,8 bis(isopropylamino)pyrimido [4,5-d] pyridazine(8) 2-pl1enyl-3,4-dihydro-5,8 bis(npropylamino)pyrimido[4,5-d]pyridazine (9) 2 phenyl3,4-dihydro-5,8-bis(N-methyl-2-hydroxyethylamino) pyrimido [4,5-dpyridazine (10) 2-phenyl-3,4-dihydro-5,S-bis(N-benzyl-Zhydroxyethylamino )pyrirnido [4,5-d] pyridazine (11)2-(4-chlorophenyl)-3,4 dihydro-5,8-dimorpholinopyrimido[4,5-d]pyridazine(12) 2 (4chlorophenyl)-3,4-dihydro-5,8-dipiperidinopyrimido[4,5-d]pyridazine (13)2-(3-tolyl)-3,4-dihydro-5,8 dimorpholinopyrimido- [4,5-d1pyridazine (14)2-(3-tolyl)-3,4-dihydro 5,8 bis(isopropylamino)- pyrimido [4,5 -d pyridazine (15) 2-(3-tolyl) 3,4-dihydro-5,8-dipiperazinopyrimido- [4,5-d]pyridazine (l6) 2 (4 chlorophenyl) 3,4-dihydro-5,8-bis(benzylamino)pyrimido [4,5-d pyridazine (17) 2-(4-chlorophenyl)-3,4-dihydro 5,8dianilinopyrimido [4,5 -d] pyridazine (18) 2-(5-naphthyl)-3,4-dihydro5,8 dimorpholinopyrimido[4,5-d]pyridazine (19) 2-(6 naphthyl)3,4-dihydro-5,8-dipiperidinopyrimido[4,5-d]pyridazine (20) 2-(B-naphthyl -3,4-dihydro-5,8-bis isopropylamino pyrimido [4,5 -d]pyridazine (21) 2-(2-furyl)-3,4-dihydro5,8 dimorpholinopyrimido-[4,5-d1pyridazine (22) 2 (Z-thienyl)-3,4-dihydro-5,8dimorpholinopyrimido [4,5-d1pyridazine (23) 2 (2pyridyl)-2,4-dihydro-5,S-dimorpholinopyrimido[4,5-d]pyridazine (24)2-phenyl-3,4-dihydro-5,8-bis(N-methyl-Z-hydroxyethylamin0)pyri mido[4,5-d} pyridazine (25) 2-phenyl-3,4-dihydro-5,8-bis(phenylamino)pyrimido 4,5-d pyridazine (26)2-phenyl-3,4-dil1ydro-5,8-bis(3,5-dimethylmorpholino)pyrimido[4,5-d1pyridazine(27) 2-phenyl-3,4-dihydro-5,8-bis(cyclohexylamino) pyrimido[4,5-d1pyridazine (28) 2-phenyl-3,4-dihydro-5,8-bis(3-methylmorpholino)pyrimido [4,5-d] pyridazine (29)2-(4-chlorophenyl)-3,4dihydro-5,8-bis(phenylamino)pyrimido[4,5-d]pyridazine(30) 2-(4-chlorophenyl)-3,4-dihydro-5,8-'bis(3,5-dimorpholino )pyrimido[4,5-d] pyridazine (3 l 2-(4-chlorophenyl -3,4-dihydro-5,8-bis(cyclohexylamino)pyrimido[4,5-d]pyridazine (32) 2- (4-chlorophenyl)-3,4-dihydro-5,8-bis (Ii-methylmorpholino) pyrimiclo [4,5-d1pyridazine(33) 2-(4-chlorophenyl)-3,4-dihydro-5,8-bis(isopropylamino) pyrimido[4,5-d1pyridazine (34) 2-(Z-furyl)-3,4-dihydro-5,8-bis(isopropylamino)pyrimido[4,5-d]pyridazine (35)2-(2-furyl)-3,4dihydro-5,8-bis(benzylamino) pyrimido [4,5-d] pyridazine(36) 2-( Z-furyl) -3,4-dihydro-5,8-bis (cyclohexylamino) Ypyrimido[4,5-d] Pyridazine (37) 2- (Z-furyl)-3,4-dihydro-S,8-dipiperidinopyrimido- [4,5-d1pyn'dazine (38) 2-(Z-furyl) -3,4-dihydro-5,8-dipyrrolidinopyrimido- [4,5-d1pyridazine (39)2- Z-thienyl) -3,4-dihydro-5,8-bis (isopropylamino) pyrimido [4,5-d]pyridazine 40) 2- Z-thienyl -3 ,4-dihydro-5,8-bis (benzylamino) pyrimido[4,5-d] pwidazine (41 2-(2-thienyl)-3,4-dihydro-5,8-bis(cyclohexylamino) pyrimido [4, 5 -d] pyridazine (42)2- (Z-thienyl -3,4-dihydro-5,S-dipiperazinopyrimido [4,5-d1pyridazine(43 2- (Z-thienyl) -3 ,4-dihydro-5,S-dipyrrolidinopyrimido[4,5-d1pyridazine (44) 2-(2-pyridyl)-3,4-dihydro-5,8-clipiperidinopyrimido [4,5-d1pyridazine (45 2-Z-pyridyl -3,4-dihydro-5,S-dipyrrolidinopyrimido [4,5 d] pyridazine (46)2- 2-pyridyl -3,4-dihydro-5,8-bis(benzylamino) pyrimido [4,5-d]pyridazine (47) 2- 2-pyridyl) -3,4-dihydro-5,8-bis (isopropylamino)pyrimido [4,5-d] pyridazine (48) 2-phenyl3 ,4-dihydro-5,8-biscyclohexylamino) pyrimido [4,5-d1pyridazine, and their 1,4-dihydroisomers.

The present compounds of the General Formula I are produced by reducinga compound of the General Formula II wherein R and R have the samemeaning as above.

The reduction of the present invention can be conducted after any of perse conventional means which have been generally used for reduction of adouble bond of CH=N to a single bond of CH NH.

The methods of the reduction may be exemplified by (I) a method whichcomprises using a reducing agent, for example, a combination of a metal(e.g. zinc, sodium, magnesium, aluminum, amalgam thereof, lithium, tin,iron) and an acid (e.g. hydrochloric acid, sulfuric acid, acetic acid),an alcohol (e.g. ethyl alcohol, methyl alcohol), alkaline substance(e.g. sodium hydroxide, liquid ammonia) or water; a low valency metalcompound (e.g. stannous chloride, ferrous sulfate, ferrous hydroxide); acompound which acts as an oxygen-acceptor (e.g. sulfide such as sodiumsulfide, ammonium sulfide, hydrogen sulfide; dithionite such as sodiumdithionite; sulfite such as sodium sulfite); a complex metal hydride(e.g. lithium aluminum hydride, lithium borohydride), (II) a catalyticreduction which comprises using hydrogen gas and a catalyst such asnoble metal catalyst (e.g. platinum oxide, palladium carbon), Raneynickel, copper chromium oxide, or (III) an electrolytic reduction. Amongthese methods, the method (I) or (II) is rather conveniently applicable.

The hydrogen gas may be employed at atmospheric pressure or at anelevated pressure.

In carrying out this catalytic reduction, temperature, pressure, timeand solvent vary with the kind of starting material to be reduced and acatalyst used, and these reaction conditions are not necessarilycritical. Practically, it is preferred to carry out this catalyticreduction by using a noble metal catalyst such as platinum oxide in asolvent such as an organic carboxylic acid (e.-g. formic acid, aceticacid) at room temperature and atmospheric pressure.

In carrying out the present reduction by using a reducing agentmentioned above, reaction conditions such as temperature, solvent ortime vary with the kind of starting material to be reduced and thereducing agent used, and they are not necessarily critical. Practically,it is preferred to carry out this reduction by using a reducing agentsuch as lithium aluminum hydride, lithium borohydride or metalic sodiumin the presence of a suitable organic solvent such as ethers (e.g. ethylether, tetrahydrofuran), alcohols (e.g. methyl alcohol, ethyl alcohol)under cooling or at a temperature ranging from room temperature to thereflux temperature of the reaction system for about 1 to about 24 hours.

Incidentally, the starting compounds represented by the General FormulaII may be produced by the steps shown in the following scheme:

wherein R and R have the same meaning as above; X stands for a halogenatom; R, R" and R are the same or ditferent and each stands for a loweralkyl group.

The following is more detailed explanation of the above respectivesteps.

The reaction of step (A) is carried out preferably in a suitable solvent(e.g. methyl alcohol, ethyl alcohol, chloroform, tetrahydrofuran, ethylacetate) and in the presence of an alkali metal alcoholate (e.g.methylate, ethylate of sodium, potassium, lithium) as a condensationagent at room temperature or under cooling.

The reaction of step (B) is carried out preferably in a suitable solvent(e.g. methyl alcohol, ethyl alcohol, tetrahydrofuran, dioxane) aroundthe boiling point of the solvent used.

An amount of hydrazine to be used in the reaction of step (B) ispreferably about 2 moles or more per mole of the Compound VI.

The reaction of step (C) is generally conducted by treating a compoundof the General Formula V with an acid at room temperature or undercooling.

As the above-mentioned acid, any of acids which can convert thehydrazinium salt of the General Formula V to the corresponding hydroxyderivative of the General Formula IV may be used.

Typical examples of the acids usable are hydrochloric acid, sulfuricacid, acetic acid. The reaction of the step (D) is generally conductedby subjecting a compound of the General Formula IV to halogenation in asuitable solvent (e.g. pyridine, dimethylsulfoxide,N,N-dimethylformamide, benzene) by heating under reflux a mixture of thecompound of the General Formula IV and a halogenating agent (e.g.phosphorus oxychloride, phosphorus pentachloride, phosphorus tribromide,phosphorus trichloride).

The reaction of step (E) is carried out by reacting a compound of theGeneral Formula HI with an amine corresponding to R of the GeneralFormula II.

The reaction is preferably conducted in a suitable solvent (e.g.acetone, methyl alcohol, ethyl alcohol, tetrahydrofuran, chloroform,ethylacetate, benzene) or by using a large excess of the above-mentionedamine around the boiling point of the solvent or an amine used.

After completion of the reaction of thi invention, the subject compoundof the General Formula I may be isolated and purified by a conventionalmethod, e.g. extraction with a suitable solvent, followed byevaporation, recrystallization or a treatment withcolumn-chromatography, etc.

When the subject compound is obtained as a free base, it may beconverted to its acid salt with an acid such as organic ones (e.g.oxalic acid, malic acid, maleic acid, tartaric acid, etc.) and inorganicones (e.g. hydrochloric acid, sulfuric acid, nitric acid, phosphoricacid, etc.).

The subject compounds of the General Formula I have effective diureticaction.

Namely, the present compounds are characterized by the followingproperties.

1) The subject compounds of this invention have effective and strongdiuretic action.

(2) The present compounds show extremely low toxicity.

(3) The present compounds induce urinary excretion of a large amount ofsodium ion, but induce urinary excretion of relatively small amount ofpotassium ion which is an essential element to human body.

Thus, the excretion ratio of urinary Na+/K+ is comparatively high in thepresent compounds.

(4) The present compounds can produce a marked additional diureticresponse in the animal undergoing maximum diuresis with known diuretics.This fact suggests that the mechanism of diuretic action of the presentcompounds is different from those of known diuretics. Thus, combinationof the present compounds with other known diuretics can produce muchincreased diuretic effect.

(5) Even when the present compounds are administered continuously for along time, substantially no side effect (e.g. increase of blood glucoselevels and blood uric acid levels) is observed.

('6) The aqueous solutions of acid salts of the present compounds arevery stable for a relatively long period of time. Therefore the presentcompounds are of great advantage to use in the form of injectablesolution.

Taking advantage of the above characteristic properties, the subjectcompounds of the present invention can be used as diuretics and areadministered for the purpose in per se or in the form of apharmaceutically acceptable composition in admixture with a suitable andconventional carrier or adjuvant.

The pharmaceutical composition may take the form of tablets, granules,powders, capsules, injections and may be administered orally orparenterally.

Usual daily doses of the compounds lie in the range of about 10 to about200 milligrams per human adult upon oral administration or about 1 toabout 20 milligrams per human adult upon injectional administration(e.g., intravenously).

The subject compounds of the present invention are 3,4- dihydroderivatives, but they can form also 1,4-dihydro isomers. There isobserved an equilibrium state between 7 the 3,4-dihydro derivatives andthe 1,4-di'hydro derivatives in a state of solution;

The equilibrium state shifts to left when the system is acidiccondition, while shifts to right when alkaline condition. The1,4-dihydro derivatives can be isolated by keeping a solution of thecompounds in water at alkaline condition. However, when the solutioncontains an organic solvent, the 1,4-dihydro derivatives can hardly beisolated, but is obtained as 3,4-dihydro derivatives.

More particularly, when the reaction mixture of the reduction process ofthis invention is subjected to a separation step, there is isolated3,4-dihydro derivatives, since the reduction is usually conducted in thepresence of an organic solvent. If thus obtained 3,4-dihydro derivativesare in the form of water-soluble salts (e.g. hydrochloride) or freebases of thus obtained 3,4-dihydro derivatives are converted into thewater-soluble salts, these water soluble salts can give a solution ofthese derivatives in water, and by adjusting this solution to alkalinecondition, for example by the addition of an alkali hydroxide, the1,4-dihydro derivatives are isolated.

The ll,4-dihydro derivatives show substantially the same pharmacologicaleffects as those of the 3,4-dihydro derivatives, and therefore the1,4-dihydro derivatives can be used as diuretics in the same field andin the same manner as those of the 3,4-dihydro derivatives.

For further explanation of the present invention, following examples aregiven wherein the word part(s) is based on Weight unless otherwisenoted, and relation between part and volume part corresponds to thatbetween gram and milliliter.

REFERENCE A mixture of 2.0 parts of2-phenyl-5,8-dich1oropyrimido[4,5-d]pyridazine and 20 parts ofmorpholine is heated on a water bath at 80 to 85 C. for 3 hours,followed by distillation under reduced pressure to remove excessmorpholine.

To the residue is added 30 volume parts of cold water, and the separatedcrystals are recrystallized from methyl alcohol to give 2.2 parts of2-phcnyl-5,S-dimorpholinopyrimido[4,5-d]pyridazine as yellow needlesmelting at higher than 300 C.

Elementary analysis.-Ca1culated for C H N O (percent): C, 63.l4; H,6.36; N, 22.09. Found (percent): C, 63.35; H, 6.34; N, 22.24.

After a similar manner to the above, the following starting materialsare produced:

1 Dewmposed.

EXAMPLE 1 To a solution of 7.56 parts of2-phenyl-5,8-dimorpholinopyrimido[4,5-d]pyridazine and 500 volume partsof acetic acid is added 0.7 part of platinum oxide. The mixture isallowed to contact under stirring with hydrogen gas at atmosphericpressure and room temperature for 40 hours, during which time 500 volumeparts of hydrogen gas is consumed.

After completion of the reaction, the catalyst is filtered off and thefiltrate is concentrated under reduced pressure. To the residue is addedvolume parts of cold water, followed by neutralization with sodiumbicarbonate. The separated crystals are recrystallized from methylalcohol to give 6.7 parts of2-phenyl-3,4-dihydro-5,8-dimorpholinopyrimido[4,5-d]pyridazine as yellowprisms melting at 246 to 247 C. (decomp:

Elementary analysis-Calculated for C H N O (percent): C, 63114; H, 6.36;N, 22.09. Found (percent): C, 63.35; H, 6.34; N, 22.25.

EXAMPLE 2 To a mixture of 1.0 part of lithium aluminum hydride and 100volume parts of ethyl ether is added 0.5 part of2-phenyl-5,S-dimorpholinopyrimido[4,5-d]pyridazine, and the wholemixture is refluxed under stirring for 5 hours.

After completion of the reaction, to the reaction mixture is added atfirst 2 volume parts of water and then 1 volume part of 6 N aqueoussolution of sodium hydroxide under cooling and stirring, followed byfiltration to remove the insolubles. The etheric solution is dried overmagnesium sulfate and concentrated to dryness. The residue is subjectedto silica-gel column-chromatography to give2-phenyl-3,4-dihydro-5,S-dimorpholinopyrimido- [4,5-d1pyridazine asyellow crystals.

Mixed examination of this product with the compound of Example 1 resultsin no melting point depression.

EXAMPLE 3 To a solution of 1.0 part of 2-phenyl-5,S-dimorpholinopyrimido[4,S-d1pyridazine and 60 volume parts of methyl alcohol is added 1.0part of sodium borohydride under cooling and stirring, followed by beingleft standing for 2 hours. After completion of the reaction, separatedcrystals are recrystallized from methyl alcohol to give 0.9 part of2-phenyl-3,4-dihydro-5,S-dimorpholinopyrimido- [4,5-d]pyridazine asyellow prisms.

Mixed examination of this product with the compound of Example 1 resultsin no melting point depression.

After a similar manner to the above, the following compounds areproduced;

Melting point Yellow prisms Orange needles.

Yellow needles.-

Decomp osed.

EXAMPLE 4 To a solution of 1.0 part of2-pl1eny1-5,8-dimorpholinopyrimido[4,5-d]pyridazine and 200 volume partsof ethyl alcohol is added 5.0 parts of metalic sodium under stirring,followed by refluxing for 10 hours. After completion of the reaction,the reaction mixture is concentrated to dryness under reduced pressure.The residue is subjected to silica-gel column-chromatography to give 0.4part of 9 2 phenyl 3,4-dihydro-5,8-dinrorpholinopyrimido[4,5-d]pyridazine as yellow crystals.

Mixed examination of this product with the compound of Example 1 resultsin no melting point depression.

EXAMPLE 5 To a 50 volume parts of weight percent hydrochloric acid isadded 10.0 parts of2-phenyl-3,4-dihydro-5,8-dimorpholinopyrimido[4,5-d]pyridazine underheating at 50 C., followed by keeping standing under ice coolingovernight. This procedure gives 8.9 parts of 2-phenyl-3,4-dihydro-S,8-dimorpholinopyrimido[4,5-d]pyridazine hydrochloride asyellow hairy crystals melting at 220 to 235 C. (decomposition).

Elementary analysis.--Calculated for C H N O Cl- 2H O (percent): C,53.03; H, 6.45; N, 18.55; Cl, 7.83. Found (percent): C, 53.10; H, 6.36;N, 18.58; Cl, 7.78.

EXAMPLE 6 Iii-( N H. l

wherein R is a member selected from the group consisting of phenyl,naphthyl and said groups substituted by alkyl of l-3 carbon atoms,halogen, morpholino, piperazine or pyrrolidino, and R representspyrrolidino, piperidino, morpholino, methylmorpholino,dimethylmorpholino, piperazino, N-methyl-piperazino, N-benzylpiperazino,monoor di-alkyl amino having 1-6 carbon atoms in each alkyl group,cyclopentylamino, cyclohexylamino, anilino, naphthylamino, benzylamino,phenylethylamino, N-methyl-Z-hydroxyethylamino or N-benzyl-Z-hydroxyethylamino, 1,4-dihydro isomers thereof and pharmaceuticallyacceptable salts thereof.

2. A compound as claimed in claim 1, wherein R is a cyclic amino group.

3. A compound as claimed in claim 1 wherein R is a monoarylamino group.

4. A compound as claimed in claim 1 wherein R is a monoaralkylaminogroup.

5. A compound as claimed in claim 1, wherein R is selected from thegroup consisting of monoalkylamino, dialkylamino andmonocycloalkylamino.

6. A compound as claimed in claim 1, wherein the compound is2-phenyl-3,4-dihydro 5,8 dimorpholinopyrimido[4,5-d]pyridazine.

7. A compound as claimed in claim 1, wherein the compound is2-(4-chlorophenyl) 3,4 dihydro-5,8-dipiperidinopyrimido [4,5-d]pyridazine.

8. A compound as claimed in claim 1, wherein the compound is 2-phenyl3,4 dihydro-5,8-dipiperidinopyrimido[4,5-d1pyridazine.

9. A compound as claimed in claim 1, wherein the compound is2-phenyl-3,4-dihydro-5,8-bis(3,5-dimethy1- morpholino pyrimido [4,5 -d]pyridazine.

10. A compound as claimed in claim 1, wherein the compound is2-(m-tolyl)-3,4-dihydro-5,8-bis(isopropylamino)pyrirnido[4,5-d]pyridazine.

11. A compound as claimed in claim 1, wherein the compound isZ-phenyl-3,4-dihydro-5,8-dianilinopyrimido- [4,5-d]pyridazine.

12. A compound as claimed in claim 1, wherein the compound is2-phenyl-3,4-dihydro-5,8-bis(benzylamino) pyrimido[4,5-d]pyridazine.

13. A compound as claimed in claim 1, wherein the compound is2phenyl-3,4-dihydro-5,8-bis(cyclohexylamino)pyrimido[4,5-d]pyridazine.

14. A compound as claimed in claim 1, wherein the compound is 2-phenyl3,4 dihydro-5,8-dimorpholinopyrimido [4,5 -d] pyridazine hydrochloride.

No references cited.

ALEX MAZEL, Primary Examiner J. TOVAR, Assistant Examiner U.S. Cl. X.R.

